Process for the synthesis of hydroxy aromatic acids

ABSTRACT

Hydroxy aromatic acids are produced in high yields and high purity (&gt;95%) from halogenated aromatic acids in a reaction mixture containing a copper source and a ligand that coordinates to copper.

TECHNICAL FIELD

This invention relates to the manufacture of hydroxy aromatic acids,which are valuable for a variety of purposes such as use asintermediates or as monomers to make polymers.

BACKGROUND

Hydroxy aromatic acids are useful as intermediates and additives in themanufacture of many valuable materials including pharmaceuticals andcompounds active in crop protection, and are also useful as monomers inthe production of polymers. Salicylic acid (o-hydroxybenzoic acid), forexample, is used in the manufacture of aspirin and has otherpharmaceutical applications. Esters of p-hydroxybenzoic acid, known as“parabens”, are used as food and cosmetic preservatives.P-hydroxybenzoic acid and 6-hydroxy-2-naphthoic acid are each used as acomponent of liquid crystalline polymers.

Various preparations of hydroxybenzoic acids, including2,5-dihydroxyterephthalic acid (“DHTA”), are known. Marzin, in Journalfuer Praktische Chemie, 1933, 138, 103-106, teaches the synthesis of2,5-dihydroxyterephthalic acid (“DHTA”) from 2,5-dibromoterephthalicacid (“DBTA”) in the presence of copper powder.

Singh et al, in Jour. Indian Chem. Soc., Vol. 34, No. 4, pages 321323(1957), report the preparation of a product that includes DHTA by thecondensation of DBTA with phenol in the presence of KOH and copperpowder.

Rusonik et al, Dalton Trans., 2003, 2024-2028, describe thetransformation of 2-bromobenzoic acid into salicylic acid, benzoic acid,and diphenoic acid in a reaction catalyzed by Cu(I) in the presence ofvarious ligands. A tertiary tetraamine minimizes the formation ofdiphenoic acid in use with Cu(I).

Comdom et al, Synthetic Communications, 32(13), 2055-59 (2002), describea process for the synthesis of salicylic acids from 2-chlorobenzoicacids. Stoichiometric amounts of pyridine (0.5 to 2.0 moles per mole of2-chlorobenzoic acid) are used such as at least 1.0 mole pyridine permole 2-chlorobenzoic acid. Cu powder is used as a catalyst along withthe pyridine.

Gelmont et al, Organic Process Research & Development, 6(5), 591-596(2002), and U.S. Pat. No. 5,703,274, describe a process for thepreparation of 5-hydroxyisophthalic acid by hydrolyzing5-bromoisophthalic acid, mixtures of 5-bromoisophthalic acid,dibromoisophthalic acid isomers, and salts thereof in an aqueousalkaline solution in the presence of a copper catalyst at a temperatureof 100 to 270° C.

Israeli Patent 112,706 discloses a process for the preparation of4-hydroxyphthalic acid, and a mixture of 3- and 4-hydroxyphthalic acids,by hydrolyzing the corresponding bromophthalic acids in an aqueousalkaline solution in the presence of a copper catalyst at a temperatureof 100 to 160° C. Examples of copper catalysts disclosed include Cu(0),CuCl, CuCl₂, Cu₂O, CuO, CuBr₂, CuSO₄, Cu(OH)₂, and copper (II) acetate.

The various prior art processes for making hydroxybenzoic acids arecharacterized by long reaction times, limited conversion resulting insignificant productivity loss, or the need to run under pressure and/orat higher temperatures (typically 140 to 250° C.) to get reasonablerates and productivity. A need therefore remains for a process by whichhydroxybenzoic acids can be produced economically; with low inherentoperational difficulty; and with high yields and high productivity insmall- and large-scale operation, and in batch and continuous operation.

SUMMARY

One embodiment of this invention provides a process for preparing ahydroxy aromatic acid that is described generally by the structure ofFormula I(COOH)_(m)—Ar—(OH)_(n)  Iwherein Ar is a C₆˜C₂₀ arylene radical, n and m are each independently anonzero value, and n+m is less than or equal to 8, by (a) contacting ahalogenated aromatic acid that is described generally by the structureof Formula II,(COOH)_(m)—Ar—(X)_(n)  IIwherein each X is independently Cl, Br or I, and Ar, n and m are as setforth above, with a base in water to form therefrom the correspondingm-basic salt of the halogenated aromatic acid in water; (b) contactingthe m-basic salt of the halogenated aromatic acid with a base in water,and with a copper source in the presence of a ligand that coordinates tocopper, to form the m-basic salt of a hydroxy aromatic acid from them-basic salt of the halogenated aromatic acid at a solution pH of atleast about 8; (c) optionally, separating the m-basic salt of thehydroxy aromatic acid from the reaction mixture in which it is formed;and (d) contacting the m-basic salt of the hydroxy aromatic acid withacid to form therefrom a n-hydroxy aromatic acid.

In another embodiment, the ligand may be an amine-ligand, the ratio ofmolar equivalents of ligand to molar equivalents of hydroxyl aromaticacid is less than or equal to about 0.1, and/or the ligand comprises,when it is a tetraamine, at least one primary or secondary amino group.

Yet another embodiment of this invention provides a process forpreparing an n-alkoxy aromatic acid by preparing an n-hydroxy aromaticacid in the manner described above and then converting the n-hydroxyaromatic acid to an n-alkoxy aromatic acid.

Yet another embodiment of this invention consequently provides a processfor preparing an n-alkoxy aromatic acid that is described generally bythe structure of Formula VI(COOH)_(m)—Ar—(OR⁹)_(n)  VIwherein Ar is a C₆˜C₂₀ arylene radical, each R⁹ is independently asubstituted or unsubstituted C₁₋₁₀ alkyl group, n and m are eachindependently a nonzero value, and n+m is less than or equal to 8, by(a) contacting a halogenated aromatic acid that is described generallyby the structure of Formula II,(COOH)_(m)—Ar—(X)_(n)  IIwherein each X is independently Cl, Br or I, and Ar, n and m are as setforth above, with a base in water to form therefrom the correspondingm-basic salt of the halogenated aromatic acid in water; (b) contactingthe m-basic salt of the halogenated aromatic acid with a base in water,and with a copper source in the presence of a ligand that coordinates tocopper, to form the m-basic salt of a hydroxy aromatic acid from them-basic salt of the halogenated aromatic acid at a solution pH of atleast about 8; (c) optionally, separating the m-basic salt of thehydroxy aromatic acid from the reaction mixture in which it is formed;(d) contacting the m-basic salt of the hydroxy aromatic acid with acidto form therefrom an n-hydroxy aromatic acid that is described generallyby the structure of Formula I,(COOH)_(m)—Ar—(OH)_(n)  Iwherein Ar, n and m are as set forth above; and (e) converting then-hydroxy aromatic acid to an n-alkoxy aromatic acid that is describedgenerally by the structure of Formula VI, wherein Ar, R⁹, n and m are asset forth above.

Yet another embodiment of this invention provides a process forpreparing a 2,5-dihydroxyterephthalic acid or a 2,5-dialkoxyterephthalicacid as described above that further includes a step of subjecting the2,5-dihydroxyterephthalic acid or the 2,5-dialkoxyterephthalic acid to areaction to prepare therefrom a compound, monomer, oligomer or polymer.

Yet another embodiment of this invention consequently provides a processfor preparing a compound, monomer, oligomer or polymer by preparing ahydroxy aromatic acid that is described generally by the structure ofFormula I(COOH)_(m)—Ar—(OH)_(n)  Iwherein Ar is a C₆˜C₂₀ arylene radical, n and m are each independently anonzero value, and n+m is less than or equal to 8, by (a) contacting ahalogenated aromatic acid that is described generally by the structureof Formula II,(COOH)_(m)—Ar—(X)_(n)  IIwherein each X is independently Cl, Br or I, and Ar, n and m are as setforth above, with a base in water to form therefrom the correspondingm-basic salt of the halogenated aromatic acid in water; (b) contactingthe m-basic salt of the halogenated aromatic acid with a base in water,and with a copper source in the presence of a ligand that coordinates tocopper, to form the m-basic salt of a hydroxy aromatic acid from them-basic salt of the halogenated aromatic acid at a solution pH of atleast about 8; (c) optionally, separating the m-basic salt of thehydroxy aromatic acid from the reaction mixture in which it is formed;(d) contacting the m-basic salt of the hydroxy aromatic acid with acidto form therefrom an n-hydroxy aromatic acid; (e) optionally, convertingthe n-hydroxy aromatic acid to a n-alkoxy aromatic acid; and (f)subjecting the n-hydroxy aromatic acid and/or the n-alkoxy aromatic acidto a reaction to prepare therefrom a compound, monomer, oligomer orpolymer.

DETAILED DESCRIPTION

This invention provides a high yield and high productivity process forpreparing a hydroxy aromatic acid as described generally by thestructure of Formula I(COOH)_(m)—Ar—(OH)_(n)  Iby contacting a halogenated aromatic acid as described generally by thestructure of Formula II(COOH)_(m)—Ar—(X)_(n)  IIwith base to form the m-basic salt of the halogenated aromatic acid;contacting the m-basic salt of the halogenated aromatic acid with base,and with a copper source in the presence of a ligand that coordinates tocopper, to form the m-basic salt of an n-hydroxy aromatic acid; and thencontacting the dibasic salt of the n-hydroxy aromatic acid with acid toform the n-hydroxy aromatic acid product.

In both Formulae I and II, Ar is a C₆˜C₂₀ arylene radical, n and m areeach independently a nonzero value, and n+m is less than or equal to 8;and in Formula II, each X is independently Cl, Br or I. The aryleneradical denoted by “—Ar—” is a multi-valent aromatic radical formed bythe removal of two or more hydrogens from different carbon atoms on thearomatic ring, or on the aromatic rings when the structure ismulticyclic. There is consequently, for example, the possibility in thearylene radical that hydrogens may be removed from two up to all sixcarbon atoms on a benzyl ring, or hydrogens may be removed from any twoand up to eight positions on either one or both rings of a naphthylradical.

The arylene radical, “Ar”, may be substituted or unsubstituted. Thearylene radical, when unsubstituted, is a univalent group containingonly carbon and hydrogen. In the arylene radical, however, one or more Oor S atoms may optionally be substituted for any one or more of thein-chain or in-ring carbon atoms, provided that the resulting structurecontains no —O—O— or —S—S— moieties, and provided that no carbon atom isbonded to more than one heteroatom. One example of a suitable aryleneradical is phenylene, as shown below.

An “m-basic salt”, as the term is used herein, is the salt formed froman acid that contains in each molecule m acid groups having areplaceable hydrogen atom.

Various halogenated aromatic acids, to be used as a starting material inthe process of this invention, are commercially available. For example,2-bromobenzoic acid is available from Aldrich Chemical Company(Milwaukee, Wis.). It can be synthesized, however, by oxidation ofbromomethylbenzene as described in Sasson et al, Journal of OrganicChemistry (1986), 51(15), 2880-2883. Other halogenated aromatic acidsthat can be used include without limitation 2,5-dibromobenzoic acid,2-bromo-5-nitrobenzoic acid, 2-bromo-5-methylbenzoic acid,2-chlorobenzoic acid, 2,5-dichlorobenzoic acid,2-chloro-3,5-dinitrobenzoic acid, 2-chloro-5-methylbenzoic acid,2-bromo-5-methoxybenzoic acid, 5-bromo-2-chlorobenzoic acid,2,3-dichlorobenzoic acid, 2-chloro-4-nitrobenzoic acid,2,5-dichloroterephthalic acid, and 2-chloro-5-nitrobenzoic acid, all ofwhich are commercially available.

Other halogenated aromatic acids useful as a starting material in theprocess of this invention include those shown in the left column of thetable below, wherein X=Cl, Br or I, and wherein the correspondinghydroxy aromatic acid produced therefrom by the process of thisinvention is shown in the right column:

(COOH)_(m)—Ar—(X)_(n) I (COOH)_(m)—Ar—(OH)_(n) II

In step (a), a halogenated aromatic acid is contacted with base in waterto form therefrom the corresponding m-basic salt of the halogenatedaromatic acid. In step (b), the m-basic salt of the halogenated aromaticacid is contacted with base in water, and with a copper source in thepresence of a ligand that coordinates to copper, to form the m-basicsalt of a hydroxy aromatic acid from the m-basic salt of the halogenatedaromatic acid.

The base used in step (a) and/or step (b) may be an ionic base, and mayin particular be one or more of a hydroxide, carbonate, bicarbonate,phosphate or hydrogen phosphate of one or more of Li, Na, K, Mg or Ca.The base used may be water-soluble, partially water-soluble, or thesolubility of the base may increase as the reaction progresses and/or asthe base is consumed. NaOH and Na₂CO₃ are preferred, but other suitableorganic bases may be selected, for example, from the group consisting oftrialkylamines (such as tributylamine);N,N,N′,N′-tetramethylethylenediamine; and N-alkyl imidazoles (forexample, N-methylimidazole). In principle any base capable ofmaintaining a pH above 8 and/or binding the acid produced during thereaction of the halogenated aromatic acid is suitable.

The specific amounts of base to be used in steps (a) and/or (b) dependon the strength of the base. In step (a), a halogenated aromatic acid ispreferably contacted with at least about m equivalents of water-solublebase per equivalent of halogenated aromatic acid. One “equivalent” asused for a base in this context is the number of moles of base that willreact with one mole of hydrogen ions; for an acid, one equivalent is thenumber of moles of acid that will supply one mole of hydrogen ions.

In step (b), enough base should be used to maintain a solution pH of atleast about 8, or at least about 9, or at least about 10, and preferablybetween about 9 and about 11. Thus, typically in step (b), the dibasicsalt of the halogenated aromatic acid is contacted with at least about nequivalents of base, such as a water-soluble base, per equivalent of them-basic salt of the halogenated aromatic acid.

In alternative embodiments, however, it may be desirable in steps (a)and (b) to use a total of at least about n+m+1 equivalents of base, suchas a water-soluble base, in the reaction mixture per equivalent of thehalogenated aromatic acid originally used at the start of the reaction.A base used in an amount as described above is typically a strong base,and is typically added at ambient temperature. The base used in step (b)may be the same as, or different than, the base used in step (a).

As mentioned above, in step (b), the m-basic salt of the halogenatedaromatic acid is also contacted with a copper source in the presence ofa ligand that coordinates to copper. The copper source and the ligandmay be added sequentially to the reaction mixture, or may be combinedseparately (for example, in a solution of water or acetonitrile) andadded together. The copper source may be combined with the ligand in thepresence of oxygen in water, or be combined with a solvent mixturecontaining water.

From the presence together in the reaction mixture of the copper sourceand the ligand, in a basic solution of the m-basic salt of thehalogenated aromatic acid, there is obtained an aqueous mixturecontaining the m-basic salt of a hydroxy aromatic acid, copperspecie(s), the ligand, and a halide salt. If desired, the m-basic saltof the hydroxy aromatic acid may, at this stage and before theacidification in step (d), be separated from the mixture [as optionalstep (c)], and may be used as an m-basic salt in another reaction or forother purposes.

The m-basic salt of the hydroxy aromatic acid is then contacted in step(d) with acid to convert it to the hydroxy aromatic acid product. Anyacid of sufficient strength to protonate the m-basic salt is suitable.Examples include without limitation hydrochloric acid, sulfuric acid andphosphoric acid.

The reaction temperature for steps (a) and (b) is preferably betweenabout 40 and about 120° C., more preferably between about 75 and about95° C.; and the process thus in various embodiments involves a step ofheating the reaction mixture. The solution is typically allowed to coolbefore the acidification in step (d) is carried out. In variousembodiments, oxygen may be excluded during the reaction.

The copper source is copper metal [“Cu(0)”], one or more coppercompounds, or a mixture of copper metal and one or more coppercompounds. The copper compound may be a Cu(I) salt, a Cu(II) salt, ormixtures thereof. Examples include without limitation CuCl, CuBr, CuI,Cu₂SO₄, CuNO₃, CuCl₂, CuBr₂, CuI₂, CuSO₄, and Cu(NO₃)₂. The selection ofthe copper source may be made in relation to the identity of thehalogenated aromatic acid used. For example, if the starting halogenatedaromatic acid is a bromobenzoic acid, CuCl, CuBr, CuI, Cu₂SO₄, CuNO₃,CuCl₂, CuBr₂, CuI₂, CuSO₄, and Cu(NO₃)₂ will be included among theuseful choices. If the starting halogenated aromatic acid is achlorobenzoic acid, CuBr, CuI, CuBr₂ and CuI₂ will be included among theuseful choices. CuBr and CuBr₂ are in general preferred choices for mostsystems. The amount of copper used is typically about 0.1 to about 5 mol% based on moles of halogenated aromatic acid.

When the copper source is Cu(0), Cu(0), copper bromide and a ligand maybe combined in the presence of air. In the case of Cu(0) or Cu(I), apredetermined amount of metal and ligand may be combined in water, andthe resulting mixture may be reacted with air or dilute oxygen until acolored solution is formed. The resulting metal/ligand solution is addedto the reaction mixture containing the m-basic salt of the halogenatedaromatic acid and base in water.

The ligand may be a straight- or branched-chain or cyclic, aliphatic oraromatic, substituted or unsubstituted, amine, or a mixture of two ofmore such ligands. Whether formed as a compound, an oligomer or polymer,conventional nomenclature may be used to describe the number of aminegroups present in the ligand, such as a mono-, di-, tri-, tetra-,penta-, hexa-, hepta- or octaamine, and so on. In its unsubstitutedform, the ligand may be an organoamine that contains carbon, nitrogenand hydrogen atoms only. In it substituted form, the amine ligand maycontain hetero atoms such as oxygen or sulfur. In various embodiments,particularly but not exclusively as relates to the tetraamines, theamine may contain at least one primary or secondary amino group.

Primary or secondary monoamines suitable for use herein as the ligandinclude those described generally by the following Formula 11

wherein R¹ and R² are each independently selected from

H;

a C₁˜C₁₀ straight-chain or branched, saturated or unsaturated,substituted or unsubstituted, hydrocarbyl radical;

a C₃˜C₁₂ cyclic aliphatic, saturated or unsaturated, substituted orunsubstituted, hydrocarbyl radical; or

a C₆˜C₁₂ aromatic substituted or unsubstituted hydrocarbyl radical.

In certain embodiments, R¹ and/or R² may for example be a methyl, ethyl,propyl, butyl, pentyl, hexyl or phenyl radical. In other embodiments, atleast one of R¹ and R² is not H. Particular monoamines suitable for useherein as the ligand include ethyl amine, isopropylamine, sec-butylamine, dimethyl amine, methyl ethyl amine, ethyl-n-butyl amine,allylamine, cyclohexyl amine, N-ethylcyclohexyl amine, aniline, N-ethylaniline, toluidine and xylidine.

Primary or secondary diamines suitable for use herein as the ligandinclude those described generally by the following Formula 12

wherein each R¹ and each R² is independently

H;

a C₁˜C₁₀ straight-chain or branched, saturated or unsaturated,substituted or unsubstituted, hydrocarbyl radical;

a C₃˜C₁₂ cyclic aliphatic, saturated or unsaturated, substituted orunsubstituted, hydrocarbyl radical; or

a C₆˜C₁₂ aromatic substituted or unsubstituted hydrocarbyl radical;

wherein R³ and R⁴ are each independently

H;

a C₁˜C₁₀ straight-chain or branched, saturated or unsaturated,substituted or unsubstituted, hydrocarbyl radical;

a C₃˜C₁₂ cyclic aliphatic, saturated or unsaturated, substituted orunsubstituted, hydrocarbyl radical; or

a C₆˜C₁₂ aromatic substituted or unsubstituted hydrocarbyl radical; or

R³ and R⁴ are joined to form a ring structure that is

a C₄˜C₁₂ aliphatic, saturated or unsaturated, substituted orunsubstituted, hydrocarbyl ring structure; or

a C₆˜C₁₂ aromatic substituted or unsubstituted hydrocarbyl ringstructure; and

wherein a, b, and c are each independently 0˜4.

In certain embodiments, one or both of the R's is H. In otherembodiments, one or both of the R²s is also H. In other embodiments, anyone or more of R¹ to R⁴ may be a methyl, ethyl, propyl, butyl, pentyl,hexyl or phenyl radical.

In various particular embodiments, a, b and c may all equal 0, andeither R³=R⁴=H, or R³ and R⁴ are joined to form an aliphatic ringstructure. Particularly when b=0, the aliphatic ring structure may be acyclohexylene group, which is the divalent radical, —C₆H₁₀—, as shownbelow, thus providing a cyclohexyl diamine:

The formation of a cyclohexylene group from R³ and R⁴ may be illustratedgenerally by the following structure:

where R¹, R², a and c are as set forth above. In alternativeembodiments, however, one amino group, or the alkyl radical on which itis located, may be in the meta or para position on the cycloalkyl oraromatic ring to the other amino group.

Suitable aliphatic diamines may include N,N′-di-n-alkylethylene diaminesand N,N′-di-n-alkylcyclohexane-1,2-diamines. Specific examples includewithout limitation N,N′-dimethylethylene diamine, N,N′-diethylethylenediamine, N,N′-di-n-propylethylene diamine, N,N′-dibutylethylene diamine,N,N′-dimethylcyclohexane-1,2-diamine,N,N′-diethylcyclohexane-1,2-diamine,N,N′-di-n-propylcyclohexane-1,2-diamine, andN,N′-dibutylcyclohexane-1,2-diamine. Examples of suitable aromaticdiamines include without limitation 1,2-phenylenediamine andN,N′-dialkylphenylene diamines such asN,N′-dimethyl-1,2-phenylenediamine andN,N′-diethyl-1,2-phenylenediamine; and benzidine.

Primary or secondary tri- and higher amines suitable for use herein asthe ligand may be described generally by the following Formula 13:

wherein each R¹, R², R³, R⁴, R⁵ and R⁶ is independently selected from;

H;

a C₁˜C₁₀ straight-chain or branched, saturated or unsaturated,substituted or unsubstituted, hydrocarbyl radical;

a C₃˜C₁₂ cyclic aliphatic, saturated or unsaturated, substituted orunsubstituted, hydrocarbyl radical; or

a C₆˜C₁₂ aromatic substituted or unsubstituted hydrocarbyl radical; and

wherein a is 2˜4, b and c is each independently 0˜4; and m≧0.

In certain embodiments, one or both of the R¹s, or at least one R³, orat least one R⁴, or R⁵, and/or R⁶ is H. In other particular embodiments,m=0, 1, 2, 3, 4 or 5. In yet other embodiments, R³=R⁴=R⁵=H; and/or oneor both of R¹ and R²=H. In further embodiments, any one or more of R¹through R⁶ may be a methyl, ethyl, propyl, butyl, pentyl, hexyl orphenyl radical.

Amines according to Formula 13 suitable for use herein as the ligandinclude, for example, those described generally by the following Formula14:

wherein x is 2˜10. Formula 14 describes various polyethyleneamineswhere, in Formula 13, each R group is H, a=2, b=c=0, and m=0 to 8.

Other amines according to Formula 13, or other higher amines, suitablefor use herein as the ligand include diethylenetriamine andtriethylenetetramine, as well as those described generally by thefollowing structures:

The ligand may also be a cyclic amine compound that is a molecule havingat least one closed ring structure in which at least one ring atom isnitrogen. This form of ligand is then heterocyclic in the sense that thering structure will contain, in addition to nitrogen atoms, other atomsthat are primarily carbon and hydrogen, but may also be oxygen and/orsulfur, as described below. The nitrogen atom may for example be amember of

a C₄˜C₁₂ aliphatic, saturated or unsaturated, substituted orunsubstituted hydrocarbyl ring structure; or

a C₅˜C₁₂ aromatic, substituted or unsubstituted hydrocarbyl ringstructure.

Examples of various nitrogen-containing, cyclic compounds suitable foruse herein as the ligand include without limitation quinolione, indole,imidazole, ethylenimine, as well as those described by the followingstructures:

Pyridine

Piperidine

1,2-bis(4-pyridyl)ethane

Bipyridyl

1,10-phenanthroline

The “hydrocarbyl” groups referred to above in the descriptions ofligands suitable for use herein are, when unsubstituted, univalentgroups containing only carbon and hydrogen. Similarly, an unsubstitutedamine is a compound that contains in its structure nitrogen, carbon andhydrogen atoms only. In any of the hydrocarbyl radicals or ringstructures described above, however, one or more O or S atoms mayoptionally be substituted for any one or more of the in-chain or in-ringcarbon atoms, provided that the resulting structure contains no —O—O— or—S—S— moieties, and provided that no carbon atom is bonded to more thanone heteroatom. An example of a suitable ligand in which an oxygen atomhas been substituted for a carbon atom is shown in Formula 15:

wherein q may have, for example, an average value of about 3 in amixture of molecules with different molecular weights.

Other examples of ligands suitable for use herein and having oxygensubstitution include anisidine, phenetidine, as well as those describedgenerally by the following structures:

Ligands of particular versatility include secondary amines, particularlyN,N′-substituted 1,2-diamines, including those that that may bedescribed as R⁷NH—(CHR⁸CHR⁹)—NHR¹⁰ wherein R⁷ and R¹⁰ are eachindependently chosen from the group of C₁-C₄ primary alkyl radicals, andR⁸ and R⁹ are each independently chosen from the group of H and C₁-C₄alkyl radicals, and/or where R⁸ and R⁹ may be joined to form a ringstructure.

When, in Formula 12, R³ and R⁴ are joined to form an aromatic ringstructure, and/or when a cyclic amine ligand contains one or morearomatic ring structures, more severe reaction conditions (e.g. highertemperature, or larger amounts of copper and/or ligand) may be needed toachieve high conversion, selectivity, yield and/or purity in thereaction.

A ligand suitable for use herein may be selected as any one or more orall of the members of the whole population of ligands described by nameor structure above. A suitable ligand may, however, also be selected asany one or more or all of the members of a subgroup of the wholepopulation, where the subgroup may be any size (1, 2, 6, 10 or 20, forexample), and where the subgroup is formed by omitting any one or moreof the members of the whole population as described above. As a result,the ligand may in such instance not only be selected as one or more orall of the members of any subgroup of any size that may be formed fromthe whole population of ligands as described above, but the ligand mayalso be selected in the absence of the members that have been omittedfrom the whole population to form the subgroup. For example, in certainembodiments, the ligand useful herein may be selected as one or more orall of the members of a subgroup of ligands that excludes from the wholepopulation pyridine, 2,5,8,11-tetramethyl-2,5,8,11-tetraazadodecane,and/or 1,1,4,7,10,10-hexamethyltriethylenetetraamine, with or withoutthe exclusion from the whole population of other ligands too.

In various embodiments, the ligand may be provided in an amount of about1 to about 8, preferably about 1 to about 2, molar equivalents of ligandper mole of copper. In those and other embodiments, the ratio of molarequivalents of ligand to molar equivalents of halogenated aromatic acidmay be less than or equal to about 0.1. As used herein, the term “molarequivalent” indicates the number of moles of ligand that will interactwith one mole of copper.

In one embodiment, a Cu(I) salt may be selected as CuBr; the ligand isselected from the group consisting of N,N′-dimethylethylene diamine,N,N′-diethylethylene diamine, N,N′-di-n-propylethylene diamine,N,N′-dibutylethylene diamine, N,N′-dimethylcyclohexane-1,2-diamine,N,N′-diethylcyclohexane-1,2-diamine,N,N′-di-n-propylcyclohexane-1,2-diamine,N,N′-dibutylcyclohexane-1,2-diamine; and CuBr is combined with two molarequivalents of the ligand in the presence of water and air.

The ligand is believed to facilitate the action of the copper source asa catalyst, and/or the copper source and the ligand are believed tofunction together to act as a catalyst, to improve one or moreattributes of the reaction.

The process described above also allows for effective and efficientsynthesis of related compounds, such as n-alkoxy aromatic acids, whichmay be described generally by the structure of Formula VI:(COOH)_(m)—Ar—(OR⁹)_(n)  VIwherein Ar, m and n are described as set forth above, and each R⁹ isindependently a substituted or unsubstituted C₁₋₁₀ alkyl group. An R⁹is, when unsubstituted, a univalent group containing only carbon andhydrogen. In any such alkyl group, however, one or more O or S atoms mayoptionally be substituted for any one or more of the in-chain carbonatoms, provided that the resulting structure contains no —O—O— or —S—S—moieties, and provided that no carbon atom is bonded to more than oneheteroatom.

An n-hydroxy aromatic acid, as prepared by the process of thisinvention, may be converted to an n-alkoxy aromatic acid, and suchconversion may be accomplished, for example, by contacting the hydroxyaromatic acid under basic conditions with an n-alkyl sulfate of theformula (R⁹)_(n)SO₄. One suitable method of running such a conversionreaction is as described in Austrian Patent No. 265,244. Suitable basicconditions for such conversion are a solution pH of at least about 8, orat least about 9, or at least about 10, and preferably about 9 to about11, using one or more bases such as described above.

In certain embodiments, it may be desired to separate the n-hydroxyaromatic acid from the reaction mixture in which it was formed beforeconverting it to an n-alkoxy aromatic acid.

The process described above also allows for effective and efficientsynthesis of products made from the resulting 2,5-dihydroxyterephthalicacid or 2,5-dialkoxyterephthalic acid such as a compound, a monomer, oran oligomer or polymer thereof. These produced materials may have one ormore of ester functionality, ether functionality, amide functionality,imide functionality, imidazole functionality, carbonate functionality,acrylate functionality, epoxide functionality, urethane functionality,acetal functionality, and anhydride functionality.

Representative reactions involving a material made by the process ofthis invention, or a derivative of such material, include, for example,making a polyester from a 2,5-dihydroxyterephthalic acid and eitherdiethylene glycol or triethylene glycol in the presence of 0.1% ofZN₃(BO₃)₂ in 1-methylnaphthalene under nitrogen, as disclosed in U.S.Pat. No. 3,047,536 (which is incorporated in its entirety as a parthereof for all purposes). Similarly, a 2,5-dihydroxyterephthalic acid isdisclosed as suitable for copolymerization with a dibasic acid and aglycol to prepare a heat-stabilized polyester in U.S. Pat. No. 3,227,680(which is incorporated in its entirety as a part hereof for allpurposes), wherein representative conditions involve forming aprepolymer in the presence of titanium tetraisopropoxide in butanol at200˜250° C., followed by solid-phase polymerization at 280° C. at apressure of 0.08 mm Hg.

A 2,5-dihydroxyterephthalic acid has also been polymerized with thetrihydrochloride-monohydrate of tetraminopyridine in strongpolyphosphoric acid under slow heating above 100° C. up to about 180° C.under reduced pressure, followed by precipitation in water, as disclosedin U.S. Pat. No. 5,674,969 (which is incorporated in its entirety as apart hereof for all purposes); or by mixing the monomers at atemperature from about 50° C. to about 110° C., and then 145° C. to forman oligomer, and then reacting the oligomer at a temperature of about160° C. to about 250° C. as disclosed in U.S. Provisional ApplicationNo. 60/665,737, filed Mar. 28, 2005 (which is incorporated in itsentirety as a part hereof for all purposes), published as WO2006/104974. The polymer that may be so produced may be apyridobisimidazole-2,6-diyl(2,5-dihydroxy-p-phenylene) polymer such as apoly(1,4-(2,5-dihydroxy)phenylene-2,6-pyrido[2,3-d: 5,6-d′]bisimidazole)polymer. The pyridobisimidazole portion thereof may, however, bereplaced by any or more of a benzobisimidazole, benzobisthiazole,benzobisoxazole, pyridobisthiazole and a pyridobisoxazole; and the2,5-dihydroxy-p-phenylene portion thereof may be replace the derivativeof one or more of isophthalic acid, terephthalic acid, 2,5-pyridinedicarboxylic acid, 2,6-naphthalene dicarboxylic acid, 4,4′-diphenyldicarboxylic acid, 2,6-quinoline dicarboxylic acid, and2,6-bis(4-carboxyphenyl)pyridobisimidazole.

EXAMPLES

The present invention is further defined in the following examples. Itshould be understood that these examples, while indicating preferredembodiments of the invention, are given by way of illustration only.From the above discussion and these examples, one skilled in the art canascertain the essential characteristics of this invention, and withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various uses andconditions.

Materials. All reagents were used as received. The ligands listed inTable 1 (labeled A through 0, and R) were obtained from Aldrich ChemicalCompany (Milwaukee, Wis.). Ligand P was obtained from TCI America(Portland, Oreg.).

TABLE 1 Ligand Purity Code Ligand (%) A N,N-Dimethylethylenediamine 95 BN,N′-Diethylethylenediamine 95 C N,N′-Dimethyl-1,6-hexanediamine 98 DN,N-Diethyl-N′-methyethylenediamine 97 E 1,2-Phenylenediamine 98 Frac-trans-N,N′-Dimethylcyclohexane-1,2- 97 diamine GN-Methylethylenediamine 95 H 1,2-Bis(4-pyridyl)ethane 99 IN,N,N′,N′-tetramethylethylenediamine 99 J rac 1,2-Diaminocyclohexane 99K N,N′-Dimethylethylenediamine 99 L 1,10-Phenanthroline  99+ MEthylenediamine diacetate 98 N N,N′-Diisopropylethylene diamine 99 O1,1,4,7,10,10- 97 Hexamethyltriethylenetetramine P(1S,2S)-(+)-Dimethylcyclohexane-1,2- 95 diamine R Bipyridyl >99 

2-bromobenzoic acid (97% purity), 2,5-dibromobenzoic acid (96% purity),2-bromo-5-nitrobenzoic acid (98% purity), 4-bromobenzoic acid (98%purity), 4-chlorobenzoic acid (99% purity), 2,4-dichloro benzoic acid(98% purity), 2,5-dichloro benzoic acid (97% purity), 2-chloro-5-nitrobenzoic acid (97% purity), 2-bromo-5-methoxy benzoic acid (98% purity)and 5-bromo-2-chloro benzoic acid (98% purity), were obtained fromAldrich Chemical Company (Milwaukee, Wis.).

2,5-dibromoterephthalic acid (95+% purity) was obtained from MaybridgeChemical Company Ltd. (Cornwall, United Kingdom). 2-bromo-5-methylbenzoic acid and 2-chloro-5-methylbenzoic acid (98% purity) wereobtained from Oakwood Products, Inc. (West Columbia, S.C., USA).2-chloro-3,5-dinitrobenzoic acid (97% purity) was obtained from AvocadoOrganics (now part of Alfa Aesar, a Johnson-Matthey Company, Ward Hill,Mass., USA).

Copper(I) bromide (“CuBr”) (98%) and copper(II) bromide (“CuBr₂”) wereobtained from Acros Organics (Geel, Belgium). Copper(II) sulfate(“CuSO₄”) (98% purity) was obtained from Strem Chemicals, Inc.(Newburyport, Mass., USA).

Acetonitrile (99.8%) and Na₂CO₃ (99.5%) were obtained from EM Science(Gibbstown, N.J.).

As used herein, the term “conversion” refers to how much reactant wasused up as a fraction or percentage of the theoretical amount. The term“selectivity” for a product P refers to the molar fraction or molarpercentage of P in the final product mix. The conversion multiplied bythe selectivity thus equals the maximum “yield” of P; the actual or“net” yield will normally be somewhat less than this because of samplelosses incurred in the course of activities such as isolating, handling,drying, and the like. The term “purity” denotes what percentage of thein-hand, isolated sample is actually the specified substance.

The terms “15% HCl” as used in the Examples denotes aqueous hydrochloricacid whose concentration is 15 grams of HCl per 100 mL of solution.Similarly, “35% HCl” denotes aqueous hydrochloric acid whoseconcentration is 35 grams of HCl per 100 mL of solution. The terms “H₂O”and “water” as used in the Examples refer to distilled water. Productpurity was determined by ¹H NMR.

The meaning of abbreviations is as follows “h” means hour(s), “min”means minute(s), “mL” means milliliter(s), “g” means gram(s), “mg” meansmilligram(s), “mmol” means millimole(s), “M” means molar, “NMR” meansnuclear magnetic resonance spectroscopy, “CONV” means conversion(percent), “SEL” means selectivity (percent), “T” means temperature, and“t” means time.

Example 1

Under nitrogen, 2.00 g (9.95 mmol) of 2-bromobenzoic acid was combinedwith 10 g of H₂O. 1.11 g (10.45 mmol) of Na₂CO₃ was then added. Themixture was heated to reflux with stirring for 30 min, remaining under anitrogen atmosphere. Another 1.58 g (14.92 mmol) of Na₂CO₃ was added tothe reaction mixture and reflux was continued for 30 min. Separately, 22mg of CuBr₂ and 28 mg of rac-trans-N,N′-dimethylcyclohexane-1,2-diamine(Ligand F) were combined with 2 mL H₂O under nitrogen to give a deeppurple solution. This solution was added to the stirred reaction mixturevia syringe at 80° C. under nitrogen and stirred for 1 h at 80° C. Aftercooling to 25° C., the reaction mixture was acidified with 15% HCl,producing a white precipitate. The white precipitate was filtered andwashed with water. After drying, a total of 1.34 g (9.7 mmol, 98% yield)salicylic acid was collected. The purity was determined by ¹H NMR to beabout 99%.

Example 2

Under nitrogen, 7.82 g (50 mmol) of 2-chlorobenzoic acid was combinedwith 31 g of H₂O. 6.62 g (62.5 mmol) of Na₂CO₃ was then added. Themixture was heated to reflux with stirring for 30 min, remaining under anitrogen atmosphere. Separately, 36 mg of CuBr and 79 mg ofrac-trans-N,N′-dimethylcyclohexane-1,2-diamine (Ligand F) were combinedwith 1 mL H₂O under nitrogen. The resulting mixture was stirred under anair atmosphere until the CuBr was dissolved to give a deep purplesolution. This solution was added to the stirred reaction mixture viasyringe at 80° C. under nitrogen and stirred for about 3 h at 100° C.and the reaction was monitored by ¹H NMR. Table 3 shows the distributionof starting material and product at different reaction times. A productselectivity of more than 99% was observed. After reaction completion,the mixture was allowed to cool to 25° C. and the reaction mixture wasacidified with 15% HCl, producing a white precipitate. The whiteprecipitate was filtered, washed with water and dried yielding 6.00 g2-hydroxybenzoic acid (85% yield). The filtrate was extracted with ethylacetate and evaporated to dryness to receive another 0.65 g of2-hydroxybenzoic acid resulting in a total yield of 6.65 g (48.2 mmol,96% yield).

TABLE 3 Progress of Example 2 2 chlorobenzoic 2-hydroxybenzoic benzoicacid acid acid SEL Time [min] 17%  82% 0% >99% 10 2% 98% 0% >99% 35 2%97% 0% >99% 65 1% 98% 0% >99% 120 

Example 3 Comparative

Under nitrogen, 7.82 g (50 mmol) of 2-chlorobenzoic acid was combinedwith 31 g of H₂O, generally following the process described in Comdom etal (above). 10.37 g (75 mmol) of K₂CO₃, 4.04 g of pyridine (about 51mmoles), and 0.25 g of copper powder were added and the mixture washeated to reflux with stirring for about 3 h. The reaction was monitoredby ¹H NMR. Table 4 shows the distribution of starting material andproduct at different reaction times. A product selectivity of between 82and 92% was observed depending on reaction time. After reactioncompletion the mixture was allowed to cool to 25° C. and the reactionmixture was acidified with 15% HCl, producing a white precipitate. Thewhite precipitate was filtered, washed with water and dried yielding5.60 g of a mixture of 2-hydroxybenzoic acid (74% mol), 2-chlorobenzoicacid (19% mol) and benzoic acid (7% mol). The filtrate was extractedwith ethyl acetate and evaporated to dryness to receive another 0.72 gof the same product resulting in a total yield of 6.32 g of crudeproduct. The net yield of 2-hydroxybenzoic acid amounted to 33.6 mmol(67%).

TABLE 4 Progress of Example 3 2-chlorobenzoic 2-hydroxybenzoic BenzoicSEL acid acid acid (%) Time [min] 91%   7% 2% 82 10 84% 14% 2% 88 35 50%46% 4% 92 65 19% 74% 7% 91 120 

Example 4

Under nitrogen, 2.00 g (9.95 mmol) of 2-bromobenzoic acid was combinedwith 10 g of H₂O. 1.11 g (10.45 mmol) of Na₂CO₃ was then added. Themixture was heated to reflux with stirring for 30 min, remaining under anitrogen atmosphere. Another 1.58 g (14.92 mmol) of Na₂CO₃ was added tothe reaction mixture and reflux was continued for 30 min. Separately, 14mg of CuBr and 28 mg of rac-trans-N,N′-dimethylcyclohexane-1,2-diamine(Ligand F) were combined with 1 mL acetonitrile under nitrogen. Theresulting mixture was stirred under an air atmosphere until the CuBr wasdissolved to give a blue solution. This solution was added to thestirred reaction mixture via syringe at 80° C. under nitrogen andstirred for 2 h at 80° C. After cooling to 25° C., the reaction mixturewas acidified with 15% HCl, producing a white precipitate. The whiteprecipitate was filtered and washed with water. After drying, a total of1.34 g (9.7 mmol, 98% yield) salicylic acid was collected. The puritywas determined by ¹H NMR to be >99%.

Example 5

Example 5 was carried out using the same procedure as in Example 1 butsubstituting an equimolar amount of CuSO₄ for the CuBr₂. After drying, atotal of 1.30 g (9.4 mmol, 95% yield) salicylic acid was collected. Thepurity was determined by ¹H NMR to be about 99%.

Examples 6, Example 7 Comparative

Under nitrogen 2 mmol of 2-bromobenzoic acid was stirred with a solutionof 3 mmol Na₂CO₃ at 80° C. until all of the acid was dissolved.Subsequently, 0.01 mmol of CuBr and either 0.02 mmol ofrac-trans-N,N′-dimethylcyclohexane-1,2-diamine (Example 6, Ligand F), or0.01 mmol of 1,1,4,7,10,10-hexamethyltriethylenetetramine [Example 7(Comparative), Ligand O] dissolved in 1 mL acetonitrile were added andthe reaction mixture was heated at 80 for 3 h. After cooling to ambienttemperature the reaction mixtures were carefully acidified with 35%aqueous HCl. The products were isolated by filtration, washed with waterand dried under vacuum. The filtrate was extracted with ethyl acetateand evaporated to dryness. The crude reaction products were analyzed by¹H NMR (d6-dmso). The results, summarized in Table 5, demonstrate thepoor performance of the tertiary tetraamine [Ligand 0 (Comparative)] inExample 7 in comparison with the N,N′-substituted 1,2-diamine ligand(Ligand F) used in Example 6.

TABLE 5 Examples 6 and 7 2-bromobenzoic 2-hydroxybenzoic Example acidacid Net yield 6  0% >99% 96% 7 95%  <5% <5% (Comparative)

Examples 8-23

Under nitrogen, 2 mmol of the halogen-substituted benzoic acid indicatedin Table 6 was stirred with a solution of 3 mmol Na₂CO₃ at 50-75° C.until all of the halogen-substituted benzoic acid was dissolved.Subsequently, 0.02 mmol CuSO₄ and 0.04 mmolrac-trans-N,N′-dimethylcyclohexane-1,2-diamine (Ligand F) dissolved in 1mL deionized water were added and the reaction mixture was heated at80-100° C. for 4 h. After cooling to ambient temperature the reactionmixtures were carefully acidified with 35% aqueous HCl.

In isolation method A, the products were extracted from the aqueouslayer twice with ethyl acetate, the ethyl acetate fractions werecombined and the crude reaction product was isolated by evaporation ofethyl acetate under vacuum. In isolation method B, the products wereisolated by filtration, washed with water and dried under vacuum. Thecrude reaction product was analyzed by ¹H NMR (d6-dmso). The results aresummarized in Table 6.

TABLE 6 Examples 8~23 Starting material Halogenated Benzoic AcidIsolation CONV SEL Example Benzoic Acid Product T (° C.) Method (%) (%)8 2,5-dibromo- 2-hydroxy-5- 80 B >99 >99 bromo- 9 2-bromo-5-nitro-2-hydroxy-5- 80 B >99 >99 nitro- 10 2-bromo-5-nitro- 2-hydroxy-5- 100A >99 >99 nitro- 11 2-bromo-5-methyl- 2-hydroxy-5- 80 B >99 >99 methyl-12 2-bromo-5-methyl- 2-hydroxy-5- 100 A >99 >99 methyl- 13 4-bromo-4-hydroxy- 100 A >99 >99 14 4-chloro- 4-hydroxy- 80 B >99 >99 152,4-dichloro- 2-hydroxy-4- 100 A 70 >99 chloro- 16 2,5-dichloro-2,5-dihydroxy- 80 B 93 >99 17 2-chloro-5-nitro- 2-hydroxy-5- 100 A74 >99 nitro- 18 2-chloro-3,5-dinitro- 2-hydroxy-3,5- 100 A >99 >99dinitro- 19 2-chloro-3,5-dinitro- 2-hydroxy-3,5- 80 B >99 >99 dinitro-20 2-chloro-5-methyl- 2-hydroxy-5- 100 A >99 >99 methyl- 21 2-bromo-5-2-hydroxy-5- 100 A >99 >99 methoxy- methoxy- 22 2-bromo-5- 2-hydroxy-5-80 B >99 >99 methoxy- methoxy- 23 2-chloro-5-bromo- 2-hydroxy-5- 80 B73 >99 bromo-

Example 24

Under nitrogen, 1.86 g (10.0 mmol) of 2-chloro-4-methylbenzoic acid wascombined with 10 g of H₂O. 1.11 g (15 mmol) of Ca(OH)₂ was then added.The mixture was heated at 85° C. under stirring for 60 min, remainingunder a nitrogen atmosphere. Separately, 43 mg of CuBr and 94 mg ofrac-trans-N,N′-dimethylcyclohexane-1,2-diamine (Ligand F) were combinedwith 1 mL deionized water under nitrogen. The resulting mixture wasstirred under an air atmosphere until the CuBr was dissolved to give ablue solution. This solution was added to the stirred reaction mixturevia syringe at 80° C. under nitrogen and stirred for 24 h at 80° C.After cooling to 25° C., the reaction mixture was acidified with 15%HCl, producing a white precipitate. The white precipitate was filteredand washed with water. After drying, a total of 1.45 g (9.5 mmol, 95%yield) of 2-hydroxy-4-methylbenzoic acid was collected. The purity wasdetermined by ¹H NMR to be >99%.

Example 25

The same procedure as described in Example 24 was performed but using2.45 g (10.0 mmol) of 4-bromoisophthalic acid as the substrate and 2.70g (25.5 mmol) of Na₂CO₃ instead of Ca(OH)₂. A total of 1.49 g (8.2 mmol,82% yield) of 4-hydroxyisophthalic acid was collected. The purity wasdetermined by ¹H NMR to be 88%.

Example 26

The same procedure as described in Example 25 was performed but using2.01 g (10.0 mmol) of 4-bromobenzoic acid as the substrate and 16 mg ofCuSO₄ as the copper source. A total of 1.13 g (7.76 mmol, 81% yield) of4-hydroxy-benzoic acid was collected. The purity was determined by ¹HNMR to be 90%.

Example 27

The same procedure as described in Example 1 was performed but using12.25 g (50.0 mmol) of 2-bromo-p-terephthalic acid as the substrate, 31g of H₂O, a total of 9.94 g (94 mmol) of Na₂CO₃, 35 mg of CuBr as thecopper source and 79 mg of Ligand F. A total of 7.9 g (39 mmol, 78%yield) of 2-hydroxy-terephthalic acid was collected. The purity wasdetermined by ¹H NMR to be 97%.

Example 28

Under nitrogen, 2.00 g (8.51 mmol) of 2,5-dichloroterephthalic acid wascombined with 10 g of H₂O. 0.938 g (8.85 mmol) of Na₂CO₃ was then added.The mixture was heated to reflux with stirring for 30 min, remainingunder a nitrogen atmosphere. Another 1.31 g (12.34 mmol) of Na₂CO₃ wasadded to the reaction mixture and reflux was continued for 30 min.Separately, 12 mg of CuBr and 24 mg ofrac-trans-N,N′-dimethylcyclohexane-1,2-diamine (Ligand F) were combinedwith 2 mL H₂O under nitrogen. The resulting mixture was stirred under anair atmosphere until the CuBr was dissolved to give a deep purplesolution. This solution was added to the stirred reaction mixture viasyringe at 80° C. under nitrogen and stirred for 20 h at 80° C. Aftercooling to 25° C., the reaction mixture was acidified with HCl (conc.),producing a dark yellow precipitate. The yellow precipitate was filteredand washed with water. After drying, a total of 1.59 g (8.03 mmol, 94%yield) 2,5-dihydroxyterephthalic acid was collected. The purity wasdetermined by ¹H NMR to be 95%.

Example 29

Under nitrogen, 2.00 g (9.95 mmol) of 3-bromobenzoic acid was combinedwith 10 g of H₂O. 1.11 g (10.45 mmol) of Na₂CO₃ was then added. Themixture was heated to reflux with stirring for 30 min, remaining under anitrogen atmosphere. Another 1.58 g (14.92 mmol) of Na₂CO₃ was added tothe reaction mixture and reflux was continued for 30 min. Separately, 14mg of CuBr and 28 mg of rac-trans-N,N′-dimethylcyclohexane-1,2-diamine(Ligand F) were combined with 2 mL water under nitrogen. The resultingmixture was stirred under an air atmosphere until the CuBr was dissolvedto give a blue solution. This solution was added to the stirred reactionmixture via syringe at 80° C. under nitrogen. The temperature wasincreased to give a steady reflux and continued to stir for 25 hr. Aftercooling to 25° C., the reaction mixture was acidified with 15% HCl,producing a white precipitate. The white precipitate was filtered andwashed with water. ¹H NMR analysis showed a conversion of 78% with aselectivity of 3-hydroxybenzoic acid of 100%. The overall yield wasdetermined to be 78%.

Examples 30-32

Under nitrogen, 10 mmol of 2-bromobenzoic acid was stirred with asolution of 12.5 mmol Na₂CO₃ in 10 mL H₂O at 50-75° C. until all of thehalogen substituted benzoic acid was dissolved. Subsequently, 0.01 mmolcopper source (CuBr or CuSO₄ as indicated in Table 7) and 0.02 mmol ofeither Ligand F or Ligand R (as indicated in Table 7), dissolved understirring with air in 1 mL deionized water, were added; and the reactionmixture was heated at the temperature and for the time noted in Table 7.After cooling to ambient temperature, the reaction mixtures wereacidified with 35% aqueous HCl. The products were isolated byfiltration, washed with water and dried under vacuum. The crude reactionproduct was analyzed by ¹H NMR (d6-dmso). The results are summarized inTable 7.

TABLE 7 Examples 30~32 Ligand CONV SEL T t Cu Ligand Example Code (%)(%) (° C.) (h) Source Structure 30 R  3% >95 80 3 CuBr

31 F >99 >98 80 3 CuBr

32 F >99 >98 80 3 CuSO₄

Examples 33˜48 Example 49 Comparative

Under a nitrogen atmosphere, to a 2 mL vial with magnetic stir bar wasadded 25 mg (0.077 mmol) of 2,5-dibromoterephthalic acid (“DBTA”),followed by 0.308 mL (0.308 mmol) of 1.0 M aqueous sodium hydroxide and0.169 mL (0.169 mmol) of 1.0 M aqueous sodium acetate. The mixture wasthen treated with 0.003 mL (0.00077 mol, 1 mol %) of 0.23 M copper(I)bromide in acetonitrile and 0.003 mL (0.00154 mmol, 2 mol %) of thediamine ligand as noted below in Table 8. For Example 50 (Comparative),no ligand was used. The reactor vial was then sealed under nitrogen andplaced in a sealed reactor block. After 3 hours at 90° C., the reactionmixture was allowed to cool to room temperature. The reaction mixturewas acidified with 15% aqueous HCl, producing a precipitate. Theprecipitate was filtered and washed with H₂O and the dried product wasanalyzed by ¹H NMR. Percent conversion of DBTA (II) for each ligand ispresented in Table 8. Selectivities for DHTA (I) and the intermediate2-bromo-5-dihydroxyterephalic acid (VII) are also presented in Table 8.

TABLE 8 Examples 33~49

Ligand CONV SEL SEL Ligand Code Example (II, %) (VII, %) (I, %)Structure A 33 >99 <1 84

B 34 >99 <1 94

C 35 92  5% 12

D 36 >99 <1 90

E 37 98  4 12

F 38 >99 <1 >98

G 39 >99 <1 82

H 40 83  9 10

I 41 >99 <1 55

J 42 >99 <1 76

K 43 >99 <1 96

L 44 >99 <1 11

M 45 >99  2 58

N 46 >99  3 49

P 47 >99 <1 99

R 48 >99 <1 75

— 49 31 32 2 No ligand (Comparative) (Comparative)

Where an embodiment of this invention is stated or described ascomprising, including, containing, having, being composed of or beingconstituted by certain features, it is to be understood, unless thestatement or description explicitly provides to the contrary, that oneor more features in addition to those explicitly stated or described maybe present in the embodiment. An alternative embodiment of thisinvention, however, may be stated or described as consisting essentiallyof certain features, in which embodiment features that would materiallyalter the principle of operation or the distinguishing characteristicsof the embodiment are not present therein. A further alternativeembodiment of this invention may be stated or described as consisting ofcertain features, in which embodiment, or in insubstantial variationsthereof, only the features specifically stated or described are present.

Where the indefinite article “a” or “an” is used with respect to astatement or description of the presence of a step in a process of thisinvention, it is to be understood, unless the statement or descriptionexplicitly provides to the contrary, that the use of such indefinitearticle does not limit the presence of the step in the process to one innumber.

Where a range of numerical values is recited herein, unless otherwisestated, the range is intended to include the endpoints thereof, and allintegers and fractions within the range. It is not intended that thescope of the invention be limited to the specific values recited whendefining a range.

1. A process for preparing a hydroxy aromatic acid that is describedgenerally by the structure of Formula I(COOH)_(m)—Ar—(OH)_(n)  I wherein Ar is a C₆˜C₂₀ arylene radical, n andm are each independently a nonzero value, and n+m is less than or equalto 8, comprising the steps of (a) contacting a halogenated aromatic acidthat is described generally by the structure of Formula II,(COOH)_(m)—Ar—(X)_(n)  II  wherein each X is independently Cl, Br or I,and Ar, n and m are as set forth above, with a base in water to formtherefrom the corresponding m-basic salt of the halogenated aromaticacid in water; (b) contacting the m-basic salt of the halogenatedaromatic acid with a base in water, and with a copper source in thepresence of an amine ligand that coordinates to copper, to form them-basic salt of a hydroxy aromatic acid from the m-basic salt of thehalogenated aromatic acid at a solution pH of at least about 8, whereinthe ratio of molar equivalents of ligand to molar equivalents of hydroxyaromatic acid is less than or equal to about 0.1, and the ligandcomprises, when it is a tetraamine, at least one primary or secondaryamino group; (c) optionally, separating the m-basic salt of the hydroxyaromatic acid from the reaction mixture in which it is formed; and (d)contacting the m-basic salt of the hydroxy aromatic acid with acid toform therefrom an n-hydroxy aromatic acid.
 2. A process according toclaim 1 wherein, in step (a), the halogenated aromatic acid is contactedwith at least about two normal equivalents of water-soluble base perequivalent of halogenated aromatic acid.
 3. A process according to claim1 wherein, in step (b), the m-basic salt of the halogenated aromaticacid is contacted with at least about two normal equivalents ofwater-soluble base per equivalent of the m-basic salt of the halogenatedaromatic acid.
 4. A process according to claim 1 wherein, in steps (a)and (b), a total of about n+m+1 normal equivalents of water-soluble baseare added to the reaction mixture per equivalent of the halogenatedaromatic acid.
 5. A process according to claim 1 wherein the coppersource comprises Cu(0), a Cu(I) salt, a Cu(II) salt, or a mixturethereof.
 6. A process according to claim 1 wherein the copper source isselected from the group consisting of CuCl, CuBr, CuI, Cu₂SO₄, CuNO₃,CuCl₂, CuBr₂, CuI₂, CuSO₄, Cu(NO₃)₂, and mixtures thereof.
 7. A processaccording to claim 1 where the ligand comprises a monoamine, diamine,triamine or a tetraamine.
 8. A process according to claim 1 where theligand comprises an N,N′-substituted diamine.
 9. A process according toclaim 7 wherein the ligand comprises an N,N′-di-n-alkylethylene diamineor an N,N′-di-n-alkylcyclohexane-1,2-diamine.
 10. A process according toclaim 1 wherein the ligand is selected from the group consisting ofN,N′-dimethylethylene diamine, N,N′-diethylethylene diamine,N,N′-di-n-propylethylene diamine, N,N′-dibutylethylene diamine,N,N′-dimethylcyclohexane-1,2-diamine,N,N′-diethylcyclohexane-1,2-diamine,N,N′-di-n-propylcyclohexane-1,2-diamine, andN,N′-dibutylcyclohexane-1,2-diamine.
 11. A process according to claim 1wherein the ligand comprises a cyclohexyl diamine.
 12. A processaccording to claim 1 wherein the ligand comprises a cyclic amine. 13.The process according to claim 1 wherein the ligand is selected from thegroup consisting of piperidine, bipyridyl, 1,10-phenanthroline, and1,2-bis(4-pyridyl)ethane.
 14. A process according to claim 1 furthercomprising a step of combining the copper source with the ligand beforeadding them to the reaction mixture.
 15. A process according to claim 8wherein the copper source comprises CuBr.
 16. A process according toclaim 1 wherein copper is provided in an amount of between about 0.1 andabout 5 mol % based on moles of halogenated aromatic acid.
 17. A processaccording to claim 1 wherein the ligand is provided in an amount ofbetween about one and about two molar equivalents per mole of copper.